Discovery of a Positron Emission Tomography Radiotracer Selectively Targeting the BD1 Bromodomains of BET Proteins

In this paper, we report the design, synthesis, and biological evaluation of the first selective bromodomain and extra-terminal domain (BET) BD1 bromodomains of the PET radiotracer [¹⁸F]PB006. The standard compound PB006 showed high affinity and good selectivity toward BRD4 BD1 (K_d = 100 nM and 29-fold selectively for BD1 over BD2) in an in vitro binding assay. PET imaging experiments in rodents were performed to evaluate the bioactivity of [¹⁸F]PB006 in vivo. A biodistribution study of [¹⁸F]PB006 in mice revealed high radiotracer uptake in peripheral tissues, such as liver and kidney, and moderate radiotracer uptake in the brain. Further blocking studies demonstrated the significant radioactivity decreasing (20–30% reduction compared with baseline) by pretreating unlabeled PB006 and JQ1, suggesting the high binding selectivity and specificity of [¹⁸F]PB006. Our study indicated that [¹⁸F]PB006 is a potent PET probe selectively targeting BET BD1, and further structural optimization of the radiotracer is still required to improve brain uptake to support neuroepigenetic imaging.     

Radiosynthesis and preliminary evaluation of an 18F-labeled tubastatin A analog for PET imaging of histone deacetylase 6

Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family because of its characteristics, namely, its cytoplasmic localization and ubiquitin binding. HDAC6 has been implicated in cancer metastasis and neurodegeneration. In the present study, we performed radiosynthesis and biological evaluation of a fluorine-18–labeled ligand [¹⁸F] 3 , which is an analog of the HDAC6-selective inhibitor tubastatin A, for positron emission tomography (PET) imaging. [¹⁸F] 3 was synthesized by a two-step reaction composed of ¹⁸F-fluorination and formation of a hydroxamic acid group. IC₅₀ values of 3 against HDAC1 and HDAC6 activities were 996 nM and 33.1 nM, respectively. A biodistribution study in mice demonstrated low brain uptake of [¹⁸F] 3 . Furthermore, bone radioactivity was stable at around 2% ID/g after injection, suggesting high tolerance to defluorination. Regarding metabolic stability, 70% of the compound was observed as the unchanged form at 30 minutes post injection in mouse plasma. A small animal PET study in mice showed that pretreatment with cyclosporine A had no effect on initial brain uptake of [¹⁸F] 3 , suggesting low brain uptake of [¹⁸F] 3 was not caused by the P-glycoprotein–mediated efflux. While PET imaging using [¹⁸F] 3 has a limitation with respect to neurodegenerative diseases, further studies evaluating its utility for certain cancers are worth evaluating.     

A New Highly Deuterated [18F]AV-45, [18F]D15FSP,for Imaging β-Amyloid Plaques in the Brain

[¹⁸F]AV-45 (florbetapir f18, Amyvid) is an FDA-approved PET imaging agent targeting Aβ plaques in the brain for diagnosis of Alzheimer’s disease (AD). Its metabolites led to a high background in the brain and large bone uptake of [¹⁸F]F^–, produced from dealkylation of the PEG chain. To slow down the in vivo metabolism, we report the design, synthesis, and evaluation of a highly deuterated derivative, [¹⁸F]D15FSP, and compared it with N-methyl-deuterated [¹⁸F]D3FSP and nondeuterated [¹⁸F]AV-45. D15FSP displayed excellent binding affinity (K_i = 7.52 nM) to Aβ aggregates. In vitro autoradiography of [¹⁸F]D15FSP, [¹⁸F]D3FSP, and [¹⁸F]AV-45 showed excellent binding to Aβ plaques in human AD brain sections. Biodistribution studies displayed lower bone uptake at 120 min for [¹⁸F]D15FSP compared to that for [¹⁸F]D3FSP and [¹⁸F]AV-45 (1.44 vs 4.23 and 4.03%ID/g, respectively). As the highly deuterated [¹⁸F]D15FSP displayed excellent Aβ binding affinity, high initial brain penetration, and lower bone retention, it might be suitable for PET imaging in detecting Aβ plaques.     

Synthesis and preliminary evaluation of 2‐arylhydroxyquinoline derivatives for tau imaging

Alzheimer's disease (AD) is the most common cause of dementia. Senile plaques, consisting of β‐amyloid, and neurofibrillary tangles (NFTs), composed of tau protein, are representative pathological hallmarks of AD. It is believed that the accumulation of NFTs precedes the onset of clinical symptoms of AD and correlates with the progression of memory dysfunction. Thus, the use of noninvasive detection techniques including radiolabeled probes and positron emission tomography (PET) will facilitate early diagnosis or staging of AD. In this study, we synthesized and evaluated novel hydroxylated 2‐arylquinoline derivatives as tau imaging PET probes. The binding affinities of compounds for tau were evaluated by fluorescent staining of the AD hippocampal section and a competitive binding assay using [¹⁸F]THK‐523. THK‐951 showed high binding affinity for tau pathology in an AD brain section and K18Δ280K fibrils (K_i = 20.7 nM); thus, we radiosynthesized a ¹¹C‐labeled THK‐951 and further studied its potential as a tau PET probe. The [¹¹C]THK‐951 demonstrated excellent kinetics in a normal mouse brain (3.23% ID/g at 2 min postinjection and 0.15% ID/g at 30 min postinjection) and showed the labeling of NFTs in an AD brain section by autoradiography assay. These findings indicate the availability of [¹¹C]THK‐951 for in vivo PET imaging of tau pathology in AD. Copyright © 2013 John Wiley & Sons, Ltd.     

Radiosynthesis and in vivo study of [18F]1‐(2‐fluoroethyl)‐4‐[(4‐cyanophenoxy)methyl]piperidine: a promising new sigma‐1 receptor ligand

The novel sigma‐1 receptor PET radiotracer [¹⁸F]1‐(2‐fluoroethyl)‐4‐[(4‐cyanophenoxy)methyl]piperidine ([¹⁸F]WLS1.002, [¹⁸F]‐2) was synthesized (n=6) by heating the corresponding N‐ethylmesylate precursor in an anhydrous acetonitrile solution containing [¹⁸F]fluoride, Kryptofix K₂₂₂ and potassium carbonate for 15 min. Purification was accomplished by reverse‐phase HPLC methods, providing [¹⁸F]‐2 in 59±8% radiochemical yield (EOB), with specific activity of 2.89±0.80 Ci/µmol (EOS) and radiochemical purity of 98.3±2.1%. Rat biodistribution studies revealed relatively high uptake in many organs known to contain sigma‐1 receptors, including the lungs, kidney, heart, spleen, and brain. Good clearance from normal tissues was observed over time. Blocking studies (60 min) demonstrated high (>80%) specific binding of [¹⁸F]‐2 in the brain, with reduction also noted in other organs known to express these sites. Copyright © 2005 John Wiley & Sons, Ltd.     

Development of novel PET probes, [18F]BCPP‐EF, [18F]BCPP‐BF,and [11C]BCPP‐EM for mitochondrial complex 1 imaging in the living brain

We developed three novel positron‐emission tomography (PET) probes, 2‐tert‐butyl‐4‐chloro‐5‐{6‐[2‐(2[¹⁸F]fluoroethoxy)‐ethoxy]‐pyridin‐3‐ylmethoxy}‐2H‐pyridazin‐3‐one ([¹⁸F]BCPP‐EF), 2‐tert‐butyl‐4‐chloro‐5‐[6‐(4‐[¹⁸F]fluorobutoxy)‐pyridin‐3‐ylmethoxy]‐2H‐pyridazin‐3‐one ([¹⁸F]BCPP‐BF), and 2‐tert‐butyl‐4‐chloro‐5‐{6‐[2‐(2‐[¹¹C]methoxy‐ethoxy)‐ethoxy]‐pyridin‐3‐ylmethoxy}‐2H‐pyridazin‐3‐one ([¹¹C]BCPP‐EM), for quantitative imaging of mitochondrial complex 1 (MC‐1) activity in vivo. These three PET probes were successfully labeled by nucleophilic [¹⁸F]fluorination or by [¹¹C]methylation of their corresponding precursor with sufficient radioactivity yield, good radiochemical purity, and sufficiently high specific radioactivity for PET measurement. The specificity of these probes for binding to MC‐1 was assessed with rotenone, a specific MC‐1 inhibitor, by a rat brain slice imaging method in vitro. Rat whole‐body imaging by small‐animal PET demonstrated that all probes showed high uptake levels in the brain as well as in the heart sufficient to image them clearly. The rank order of uptake levels in the brain and the heart just after injection was as follows: high in [¹⁸F]BCPP‐BF, intermediate in [¹¹C]BCPP‐EM, and low in [¹⁸F]BCPP‐EF. The kinetics of [¹⁸F]BCPP‐EF and [¹¹C]BCPP‐EM provided a reversible binding pattern, whereas [¹⁸F]BCPP‐BF showed nonreversible accumulation‐type kinetics in the brain and heart. Metabolite analyses indicated that these three compounds were rapidly metabolized in the plasma but relatively stable in the rat brain up to 60 min post‐injection. The present study demonstrated that [¹⁸F]BCPP‐EF could be a useful PET probe for quantitative imaging of MC‐1 activity in the living brain by PET.     

Novel 64Cu-Labeled CUDC-101 for in Vivo PET Imaging of Histone Deacetylases

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Radiosynthesis and biological evaluation of the new PDE10A radioligand [18F]AQ28A

Cyclic nucleotide phosphodiesterase 10A (PDE10A) regulates the level of the second messengers cAMP and cGMP in particular in brain regions assumed to be associated with neurodegenerative and psychiatric diseases. A better understanding of the pathophysiological role of the expression of PDE10A could be obtained by quantitative imaging of the enzyme by positron emission tomography (PET). Thus, in this study we developed, radiolabeled, and evaluated a new PDE10A radioligand, 8‐bromo‐1‐(6‐[¹⁸F]fluoropyridin‐3‐yl)‐3,4‐dimethylimidazo[1,5‐a ]quinoxaline ([¹⁸F] AQ28A ). [¹⁸F] AQ28A was radiolabeled by both nucleophilic bromo‐to‐fluoro or nitro‐to‐fluoro exchange using K[¹⁸F]F‐K_2.2.2‐carbonate complex with different yields. Using the superior nitro precursor, we developed an automated synthesis on a Tracerlab FX F‐N module and obtained [¹⁸F] AQ28A with high radiochemical yields (33 ± 6%) and specific activities (96‐145 GBq·μmol⁻¹) for further evaluation. Initially, we investigated the binding of [¹⁸F] AQ28A to the brain of different species by autoradiography and observed the highest density of binding sites in striatum, the brain region with the highest PDE10A expression. Subsequent dynamic PET studies in mice revealed a region‐specific accumulation of [¹⁸F] AQ28A in this region, which could be blocked by preinjection of the selective PDE10A ligand MP‐10. In conclusion, the data suggest [¹⁸F] AQ28A is a suitable candidate for imaging of PDE10A in rodent brain by PET.     

In vivo visualization of donepezil binding in the brain of patients with Alzheimer's disease

Aims

The aims of this study were to visualize in vivo binding of donepezil to acetylcholinesterase (AChE) in the brain and to establish a method for measuring the amount of binding of orally administered donepezil.

Methods

[5-¹¹C-methoxy]-donepezil ([¹¹C]-donepezil) was radiolabelled as a positron emission tomography (PET) tracer. The biodistribution of [¹¹C]-donepezil was measured by PET in 10 AD patients and six elderly normal subjects. Two AD patients underwent additional PET measurements after oral administration of donepezil for 6 months.

Results

[¹¹C]-donepezil-PET images demonstrated high densities of tracer distribution in AChE-rich brain regions such as the striatum, thalamus, and cerebellum. Compared with elderly normal subjects, patients with mild AD exhibited about 18–20% reduction of donepezil binding in the neocortex and hippocampus, while patients with moderate AD exhibited about 24–30% reduction of donepezil binding throughout the brain. Orally administered donepezil (5 mg day⁻¹) induced 61.6–63.3% reduction of donepezil binding in AD brains. The distribution volume of [¹¹C]-donepezil in the hippocampus was significantly correlated with MMSE scores in AD patients.

Conclusions

[¹¹C]-donepezil-PET enables quantitative measurement of donepezil binding in the brain. AD patients exhibited reduction of donepezil binding in the brain, even in the early stage of disease. Longitudinal evaluation by this technique enables determination of AChE binding occupancy of orally administered donepezil.

What is already known about this subject

• Deficit in central cholinergic neurotransmission is a consistent change associated with Alzheimer''s disease (AD).
• Donepezil hydrochloride exhibits selective inhibition of acetylcholinesterase (AChE) and is widely used for the treatment of AD.
• The biodistribution of donepezil in the brain after administration is not precisely understood in vivo.
• There is no method to measure the amount of binding of orally administered donepezil to AChE.

What this study adds

• This study clearly visualizes the distribution of donepezil in human brain using [¹¹C]-donepezil and positron emission tomography.
• This study demonstrates prominent reduction of the donepezil binding site in the AD brain.
• This study provides methodology to measure the AChE binding occupancy of orally administered donepezil and provides a new surrogate marker for evaluation and prediction of response to donepezil treatment.

     

Biodistribution, pharmacokinetics and metabolism of interleukin-1 receptor antagonist (IL-1RA) using [¹⁸F]-IL1RA and PET imaging in rats

BACKGROUND AND PURPOSE

Positron emission tomography (PET) has the potential to improve our understanding of the preclinical pharmacokinetics and metabolism of therapeutic agents, and is easily translated to clinical studies in humans. However, studies involving proteins radiolabelled with clinically relevant PET isotopes are currently limited. Here we illustrate the potential of PET imaging in a preclinical study of the biodistribution and metabolism of ¹⁸F-labelled IL-1 receptor antagonist ([¹⁸F]IL-1RA) using a novel [¹⁸F]-radiolabelling technique.

EXPERIMENTAL APPROACH

IL-1RA was radiolabelled by reductive amination on lysine moieties with [¹⁸F]fluoroacetaldehyde. Sprague-Dawley rats were injected intravenously with [¹⁸F]IL-1RA and imaged with a PET camera for 2 h. For the study of IL-1RA metabolites by ex vivoγ-counting of samples, rats were killed 20 min, 1 h or 2 h after injection of [¹⁸F]IL-1RA.

KEY RESULTS

[¹⁸F]IL-1RA distribution into the major organs of interest was as follows: kidneys >> liver > lungs >> brain. In lungs and liver, [¹⁸F]IL-1RA uptake peaked within 1 min post-injection then decreased rapidly to reach a plateau from 10 min post-injection. In the brain, the uptake exhibited slower pharmacokinetics with a smaller post-injection peak and a plateau from 6 min onward. IL-1RA was rapidly metabolized and these metabolites represented ∼40% of total activity in plasma and ∼80% in urine, 20 min after injection.

CONCLUSIONS AND IMPLICATIONS

Preclinical PET imaging is a feasible method of assessing the biodistribution of new biological compounds of therapeutic interest rapidly. The biodistribution of [¹⁸F]IL-1RA reported here is in agreement with an earlier study suggesting low uptake in the normal brain, with rapid metabolism and excretion via the kidneys.     

Efficient radiosynthesis and preclinical evaluation of [18F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

Herein we report an efficient radiolabeling of a ¹⁸F-fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF-1R). [¹⁸F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper-mediated ¹⁸F-fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [¹⁸F]FOMPyD showed moderate brain permeability in wild-type rats (SUV_max = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC_40–90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [¹⁸F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self-blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF-1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [¹⁸F]FOMPyD as a PET tracer for brain imaging, the concomitant one-pot copper-mediated ¹⁸F-fluorination/Boc-deprotection is a practical technique for the automated radiosynthesis of acid-sensitive PET tracers.     

Structure–Activity Relationships and in Vivo Evaluation of Quinoxaline Derivatives for PET Imaging of β-Amyloid Plaques

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Discovery of a highly specific 18F-labeled PET ligand for phosphodiesterase 10A enabled by novel spirocyclic iodonium ylide radiofluorination

As a member of cyclic nucleotide phosphodiesterase (PDE) enzyme family, PDE10A is in charge of the degradation of cyclic adenosine (cAMP) and guanosine monophosphates (cGMP). While PDE10A is primarily expressed in the medium spiny neurons of the striatum, it has been implicated in a variety of neurological disorders. Indeed, inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system (CNS) pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component. A PDE10A-targeted positron emission tomography (PET) radioligand would enable a better assessment of the pathophysiologic role of PDE10A, as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate, thus accelerating the development of effective PDE10A inhibitors. In this study, we designed and synthesized a novel ¹⁸F-aryl PDE10A PET radioligand, codenamed [¹⁸F]P10A-1910 ([¹⁸F]9), in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination. [¹⁸F]9 possessed good in vitro binding affinity (IC₅₀ = 2.1 nmol/L) and selectivity towards PDE10A. Further, [¹⁸F]9 exhibited reasonable lipophilicity (logD = 3.50) and brain permeability (P_app > 10 × 10⁻⁶ cm/s in MDCK-MDR1 cells). PET imaging studies of [¹⁸F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics. Preclinical studies in rodents revealed an improved plasma and brain stability of [¹⁸F]9 when compared to the current reference standard for PDE10A-targeted PET, [¹⁸F]MNI659. Further, dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of [¹⁸F]9 for evaluating target occupancy in vivo in higher species. In conclusion, our results indicated that [¹⁸F]9 is a promising PDE10A PET radioligand for clinical translation.KEY WORDS: Phosphodiesterase 10A, PET radioligand, ¹⁸F, Spirocyclic iodonium ylide, Nonhuman primate, Target occupancy     

Targeting Metal-Aβ Aggregates with Bifunctional Radioligand [11C]L2-b and a Fluorine-18 Analogue [18F]FL2-b

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[18F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models

Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an ¹⁸F-labeled MAGL inhibitor ([¹⁸F]MAGL-4-11) for PET imaging and demonstrated highly specific binding in vitro and in vivo. In this study, we determined [¹⁸F]MAGL-4-11 PET enabled imaging MAGL levels in the bile duct ligation (BDL) and carbon tetrachloride (CCl₄) models of liver cirrhosis; we also assessed the hepatic gene expression of the enzymes involved with EC system including MAGL, NAPE-PLD, FAAH and DAGL that as a function of disease severity in these models; [¹⁸F]MAGL-4-11 autoradiography was performed to assess tracer binding in frozen liver sections both in animal and human. [¹⁸F]MAGL-4-11 demonstrated reduced PET signals in early stages of fibrosis and further significantly decreased with disease progression compared with control mice. We confirmed MAGL and FAAH expression decreases with fibrosis severity, while its levels in normal liver tissue are high; in contrast, the EC synthetic enzymes NAPE-PLD and DAGL are enhanced in these different fibrosis models. In vitro autoradiography further supported that [¹⁸F]MAGL-4-11 bound specifically to MAGL in both animal and human fibrotic liver tissues. Our PET ligand [¹⁸F]MAGL-4-11 shows excellent sensitivity and specificity for MAGL visualization in vivo and accurately reflects the histological stages of liver fibrosis in preclinical models and human liver tissues.     

A novel synthesis of 6′′‐[18F]‐fluoromaltotriose as a PET tracer for imaging bacterial infection

The aim of this study was to develop a positron emission tomography (PET) tracer to visualize and monitor therapeutic response to bacterial infections. In our continued efforts to find maltose based PET tracers that can image bacterial infections, we have designed and prepared 6′′‐[¹⁸F]fluoromaltotriose as a second generation PET imaging tracer targeting the maltodextrin transporter of bacteria. We have developed methods to synthesize 6′′‐deoxy‐6′′‐[¹⁸F]fluoro‐α‐D‐glucopyranosyl‐(1‐4)‐O‐α‐D‐glucopyranosyl‐(1‐4)‐O‐D‐glucopyranose (6′′‐[¹⁸F]‐fluoromaltotriose) as a bacterial infection PET imaging agent. 6′′‐[¹⁸F]fluoromaltotriose was prepared from precursor, 2′′,3′′,4′′‐tri‐O‐acetyl‐6′′‐O‐nosyl‐α‐D‐glucopyranosyl‐(1‐4)‐O‐2′,3′,6′‐tri‐O‐acetyl‐α‐D‐glucopyranosyl‐(1‐4)‐1,2,3,6‐tetra‐O‐acetyl‐D‐glucopyranose (per‐O‐acetyl‐6′′‐O‐nosyl‐maltotriose 4 ). This method utilizes the reaction between precursor 4 and anhydrous [¹⁸F]KF/Kryptofix 2.2.2 in dimethylformamide (DMF) at 85°C for 10 minutes to yield per‐O‐acetyl‐6′′‐deoxy‐6‐′′ [¹⁸F]‐fluoromaltotriose ( 7) . Successive acidic and basic hydrolysis of the acetyl protecting groups in 7 produced 6′′‐[¹⁸F]fluoromaltotriose ( 8 ). Also, cold 6′′‐ [¹⁹F]fluoromaltotriose was prepared from per‐O‐acetyl‐6′′‐hydroxymaltotriose via a diethylaminosulfur trifluoride reaction followed by a basic hydrolysis. A successful synthesis of 6′′‐[¹⁸F]‐fluoromaltotriose has been accomplished in 8 ± 1.2% radiochemical yield (decay corrected). Total synthesis time was 120 minutes. Serum stability of 6′′‐[¹⁸F]fluoromaltotriose at 37°C indicated that 6′′‐[¹⁸F]‐fluoromaltotriose remained intact up to 2 hours. In conclusion, we have successfully synthesized 6′′‐[¹⁸F]‐fluoromaltotriose via direct fluorination of an appropriate precursor of a protected maltotriose.     

Improved synthesis of 4‐[18F]fluoro‐m‐hydroxyphenethylguanidine using an iodonium ylide precursor

Fluorine‐18 labeled hydroxyphenethylguanidines were recently developed in our laboratory as a new class of PET radiopharmaceuticals for quantifying regional cardiac sympathetic nerve density in heart disease patients. Studies of 4‐[¹⁸F]fluoro‐m‐hydroxyphenethylguanidine ([¹⁸F]4F‐MHPG) and 3‐[¹⁸F]fluoro‐p‐hydroxyphenethylguanidine ([¹⁸F]3F‐PHPG) in human subjects have shown that these radiotracers can be used to generate high‐resolution maps of regional sympathetic nerve density using the Patlak graphical method. Previously, these compounds were synthesized using iodonium salt precursors, which provided sufficient radiochemical yields for on‐site clinical PET studies. However, we were interested in exploring new methods that could offer significantly higher radiochemical yields. Spirocyclic iodonium ylide precursors have recently been established as an attractive new approach to radiofluorination of electron‐rich aromatic compounds, offering several advantages over iodonium salt precursors. The goal of this study was to prepare a spirocyclic iodonium ylide precursor for synthesizing [¹⁸F]4F‐MHPG and evaluate its efficacy in production of this radiopharmaceutical. Under optimized automated reaction conditions, the iodonium ylide precursor provided radiochemical yields averaging 7.8% ± 1.4% (n = 8, EOS, not decay corrected), around threefold higher than those achieved previously using an iodonium salt precursor. With further optimization and scale‐up, this approach could potentially support commercial distribution of [¹⁸F]4F‐MHPG to PET centers without on‐site radiochemistry facilities.     

Current status of PET-imaging probes of β-amyloid plaques

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by progressive cognitive decline and memory loss. One of pathological hallmarks of AD is the accumulation and deposition of β-amyloid (Aβ) plaques which is a potential target for the early diagnosis of AD. Positron emission tomography (PET), a sensitive radionuclide imaging technique, has provided opportunities to detect Aβ plaques of AD. PET-imaging probes of Aβ plaques have been extensively developed during the last decade. [¹⁸F]Florbetapir, the ¹⁸F-labeled PET-imaging probe of Aβ plaques, was recently approved by US Food and Drug Administration. A number of follow-on PET-imaging probes are currently being developed in academia and pharmaceutical companies. This article will discuss the recent development of PET-imaging probes from [¹¹C]PIB to [¹⁸F]Florbetapir, which are in clinic trials, and several follow-on probes in preclinical stage.     

A Novel 18F-Labeled Imidazo[2,1-b]benzothiazole (IBT) for High-Contrast PET Imaging of β-Amyloid Plaques

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F-18 stilbenes as PET imaging agents for detecting beta-amyloid plaques in the brain

Imaging agents targeting beta-amyloid (Abeta) may be useful for diagnosis and treatment of patients with Alzheimer's disease (AD). Compounds 3e and 4e are fluorinated stilbene derivatives displaying high binding affinities for Abeta plaques in AD brain homogenates (Ki = 15 +/- 6 and 5.0 +/- 1.2 nM, respectively). In vivo biodistributions of [18F]3e and [18F]4e in normal mice exhibited excellent brain penetrations (5.55 and 9.75% dose/g at 2 min), and rapid brain washouts were observed, especially for [18F]4e (0.72% dose/g at 60 min). They also showed in vivo plaque labeling in APP/PS1 or Tg2576 transgenic mice, animal models for AD. Autoradiography of postmortem AD brain sections and AD homogenate binding studies confirmed the selective and specific binding properties to Abeta plaques. In conclusion, the preliminary results strongly suggest that these fluorinated stilbene derivatives, [18F]3e and [18F]4e, are suitable candidates as Abeta plaque imaging agents for studying patients with AD.